Recent data implicate periodontitis as a risk factor for a number of systemic conditions but mechanisms whereby periodontal infections mediate systemic responses are not clear. We have noted that patients with periodontitis have elevated serum levels of antiphospholipid antibodies. Such antibodies, including beta 2 glycoprotein 1-dependant anti-cardiolipin (anti-CL) are present in patients with autoimmune diseases such as SLE and the Antiphospholipid Syndrome and may be induced by a variety of microbial infections. These antibodies function to induce a prothrombotic state and can cause stroke, early atherosclerosis, and adverse pregnancy outcomes such as fetal involution, prematurity, and low birth weight. The similarity between these sequelae of elevated anti-CL and putative sequelae of periodontal infection have led us to further study these antibodies in periodontitis patients. We have observed that there are significant associations between elevated levels of anti-CL and elevated serum concentrations of cell-adhesion molecules such as sVCAM-1 and sE- selectin in periodontitis patients, even in non-smokers. Furthermore, in generalized aggressive periodontitis (GAgP) patients, elevated anti-CL are associated with elevated serum sICAM-1, sVCAM-1, sE-selectin, and CRP, indicating that such patients demonstrated elevated systemic measures of vascular inflammation. We propose to determine whether anti-CL in aggressive periodontitis patients are pathogenic by testing purified antibodies in in vitro systems employing endothelial cells and macrophages. Additionally, we will determine if resolution of periodontal infection in GAgP by aggressive therapy also decreases both anti-CL and inflammatory mediator levels. We will examine additional markers of vascular inflammation and thrombosis to determine the pathways whereby anti-CL in periodontitis patients may influence systemic inflammation. Finally, we will assess the ability of periodontal disease pathogens to induce pathogenic anti-CL by immunizing mice with bacteria containing putative cross-reactive peptide sequences to beta2GP1 and testing resultant antibodies for pathogenicity. These studies may explain why some subsets of periodontitis patients are at increased risk for diseases characterized by vascular inflammation, such as atherosclerosis, stroke, and adverse pregnancy outcomes. They will also suggest applications of available diagnostic tests for antiphospholipids in periodontitis patients as well as beneficial therapeutic approaches. Recent data indicate that periodontal disease can influence parameters of systemic health but the mechanisms whereby this occurs are not clear. Our studies will examine the ability of bacteria in the oral cavity to promote production of an antibody that is known to induce vascular inflammation and procoagulant activity in other diseases. Should this prove to be an important mechanism linking the oral microflora with other parts of the body, laboratory tests routinely administered to patients with diseases such as systemic lupus erythematosis could be readily applied to periodontitis patients to predict risk for systemic sequelae, and supportive or preventive care could be systematically applied. [unreadable] [unreadable] [unreadable]